There are several patents describing benzodiazepine or dihydropyridine derivatives for treating Central Nervous System diseases. In such cases, however, no description is made of the fusion of these nucleuses to form a new pharmacologic entity. Patents using different substituents of the benzodiazepine nucleus, having no relation with the subject matter of our invention are listed below:
Patents EP1593683 and EP1157992 describe the process of obtaining molecules derived from dihydro-2,3-benzodiazepine as potential anticonvulsants, but use hydrogen-type substituents, alkyl chains, and aromatic rings of the phenyl, thienyl, furyl, pyridyl, imidazolinyl, benzimidazolyl, benzothiazole, and pthalazinyl type. Patent EP-349949 describes benzodiazepine-substituted derivatives with heterocyclic groups substituted in turn with aryl, hydroxyl, and carboxyl groups. Patent US20040157833, describes pharmaceutical compounds based on 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7-methoxy-8-hidroxy-5H-2,3-benzodiazepine.
Patent US20020103371 describes benzodiazepine derivatives modulating the GABA receptor, but does not mention the dihydropyridines.
Patent EP-733634 describes new molecular entities derived from thieno(2,3-B)(1,5) benzodiazepine.
Other patents disclosing benzodiazepine derivatives are the following: U.S. Pat. No. 5,658,901 (yielding 2,3-dihydro-1-(2,2,2-trifluoroethyl)-2-oxo-5-phenyl-1H-1,4 benzodiazepines); U.S. Pat. No. 5,610,158 (yielding 4-oxo- and 4H-imidazo(5,1-c)(1,4)benzoxazines); EP-558104 and GB9201180 (1,5-Benzodiazepine derivatives); EP-491218 (benzodiazepinone derivatives).
Diazepine synthetic variants fused with dihydropyridines, the subject matter of our invention, showed some kind of action upon the Vascular and Central Nervous Systems. However, the degree of the action depends on the nature of the R substituent at the 4-position of the 1,4-DHP and the nature of R1 substituent.
General experimental conditions: NMR-1H and NMR-13C spectra, were registered at 25° C. in a Bruker DPX300 spectrometer (300 MHz-1H, 75.4 MHz-13C) in DMSO-d6. Mass spectra were obtained with a Hewlett Packard 5989 A purity study was done using a CAMAG TLC-SCNNER II densitometer (Switzerland) (λ=254 nm).